熊果酸/甘草次酸-尿嘧啶核苷缀合物的合成与抗肿瘤活性评价  

Synthesis and Anti-tumor Activities of Ursolic Acid and Glycyrrhetinic Acid-Uridine Conjugates

作　　者：孙立 初相伍[1,2] 刘春梅 张琚政 程克光 SUN Li;CHU Xiangwu;LIU Chunmei;ZHANG Juzheng;CHENG Keguang(State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources(Guangxi Normal University),Guilin Guangxi 541004,China;School of Chemistry and Pharmacy,Guangxi Normal University,Guilin Guangxi 541004,China)

机构地区：[1]省部共建药用资源化学与药物分子工程国家重点实验室(广西师范大学),广西桂林541004 [2]广西师范大学化学与药学学院,广西桂林541004

出　　处：《广西师范大学学报（自然科学版）》2020年第1期87-92,共6页Journal of Guangxi Normal University:Natural Science Edition

基　　金：国家自然科学基金(21562006);广西自然科学基金(2015GXNSFAA139186);广西医药产业人才小高地项目(1506);药用资源化学与药物分子工程教育部重点实验室资助课题(CMEMR2013-A01,CMEMR2013-C02)

摘　　要：合成新型熊果酸和甘草次酸-尿嘧啶核苷缀合物,并研究其体外抗肿瘤活性。以熊果酸和甘草次酸为原料,在碱性条件下,与二溴烷烃反应生成溴代烷烃酯;继而与尿嘧啶核苷发生亲核取代反应,共合成得到4个新型的熊果酸/甘草次酸-尿嘧啶核苷缀合物,并采用MTT法测试其抗肿瘤活性。结果表明,甘草次酸-尿嘧啶核苷缀合物对人肝癌细胞HepG-2和人肺癌细胞A549的抑制作用比熊果酸-尿嘧啶核苷缀合物强;4个目标化合物均对人胃癌细胞BGC-823具有较好的抑制作用([(3-尿嘧啶核苷酸)-正辛基]-甘草次酸酯活性最高,20μmol/L抑制率约64%),而对NCI-H460、BEL-7404等肿瘤细胞抑制作用不明显;化合物([(3-尿嘧啶核苷基)-正辛基]-熊果酸酯对人宫颈癌细胞HeLa表现出较好的抑制作用(20μmol/L抑制率约54%)。To synthesize some novel ursolic acid/glycyrrhetinic acid-uridine conjugates and evaluate their anti-tumor activity in vitro. Ursolic acid and glycyrrhetinic acid was esterified with corresponding α,ω-dibromoalkane in the presence of potassium carbonate to prepare intermediates. Then, the intermediates were treated with uridine under potassium carbonate by means of a nucleophilic substitution reaction to generate four ursolic acid/glycyrrhetinic acid-uridine derivatives. Anti-tumor activity was tested by the MTT assay. Glycyrrhetinic acid-uridine derivatives showed better inhibitory activity against proliferation of HepG-2 and A549 cells than ursolic acid-uridine derivatives. All targeted compounds exhibited excellent inhibitory activity([n-(uridinyl-3) octyl]-3β-hydroxy-11-oxo-olean-12-en-29-oate expressed the best inhibition at about 64%), while they exhibited no obvious inhibitory effect on other tumor cells(HeLa, NCI-H460, BEL-7404). Compound [n-(uridinyl-3) octyl]-3β-hydroxyurs-12-en-28-oate showed moderate inhibitory against HeLa cells(about 54%).

关 键 词：熊果酸 甘草次酸 尿嘧啶核苷 缀合物 抗肿瘤 

分 类 号：R914.5[医药卫生—药物化学]